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STEM CELL BIOLOGY

USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression

Leukemia volume 38, pages 2466–2478 (2024)Cite this article

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Abstract

Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. Usp4 deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. Usp4 inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression.

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Fig. 1: USP4 is localized in nucleolus and upregulated during HSCs proliferation.
Fig. 2: Usp4 deletion impairs hematopoietic reconstitution capacity of HSCs.
Fig. 3: USP4 is required for HSC proliferation in response to regeneration.
Fig. 4: USP4 regulates ribosome biogenesis and protein synthesis in HSPCs.
Fig. 5: USP4 regulates HSC function by stabilizing PES1.
Fig. 6: USP4 inhibition suppresses myeloid leukemia progression.
Fig. 7: USP4 regulates ribosome biogenesis and protein synthesis in leukemia cells through PES1.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or Supplementary Materials. The sequencing datasets used in this study were derived from the NCBI Gene Expression Omnibus (GEO) database (GSE179415 and GSE164283).

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [82030039, 92049304 and 82230047], the Guangdong Basic and Applied Basic Research Foundation [2023A1515010927], the National Key Research and Development Program of China [2022YFA1103503, 2021YFA1100103 and 2020YFA0112404], the Program for Guangdong Introducing Innovative and Entrepreneurial Teams [2017ZT07S347], the innovation team project of universities in Guangdong province [2023KCXTD004].

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  1. These authors contributed equally: Bo Liu, Xianli Zhang.

Authors and Affiliations

  1. Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Bo Liu, Xianli Zhang, Yuanyuan Zhou, Haiping Liu, Zhenkun Wang, Yuting Fu, Qiongdan Gao & Zhenyu Ju

  2. Department of Hematology, Children’s Hospital, Capital Institute of Pediatrics, 100020, Beijing, China

    Xiang Cheng

  3. Fertility Preservation Lab, Guangdong-Hong Kong Metabolism and Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China

    Qingyuan Sun

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Contributions

BL and ZYJ designed the study. XLZ, BL, YYZ, HPL, ZKW and YTF performed experiments and analyzed data. BL, XLZ and ZYJ wrote the paper. QDG, XC and QYS provided additional expertise. BL and ZYJ supervised the study.

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Correspondence to Bo Liu or Zhenyu Ju.

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Liu, B., Zhang, X., Zhou, Y. et al. USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression. Leukemia 38, 2466–2478 (2024). https://doi.org/10.1038/s41375-024-02338-z

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